Over a lifetime there is an increasing potential for the development of skin cancer. It is estimated that over the lifetime 20% of United States population will develop skin cancer. A major external risk factor is sunlight. While basal cell and squamous cell carcinomas represent the majority of skin cancer cases, the leading cause of death due to skin cancer is malignant melanoma. There were 51,400 cases of melanoma in the United States in 2001, with 7800 deaths. The cure rates for basal cell and squamous cell carcinomas in developed countries is around 90% or higher. The prognosis for melanoma is less favorable; taking all age groups together, a little over 50% of patients with stage 1 disease (early stage disease) will survive 5 years free of recurrence. However, patients with disseminated disease have a median survival of less than 6 months. Clearly, of the various forms of skin cancers, malignant melanoma is the one that is the most dangerous.
Currently, the treatment of melanoma consists of local excision with a 0.5-1 cm surgical margin often associated with regional lymph node dissection. Other therapies, often combined with surgery, include radiotherapy, chemotherapy, immunotherapy (dendritic cells and immune vaccines), biological response modifiers (such as interleukin-2) and hypothermia. The treatment for other skin cancers consists of mainly surgical excision; other treatments include electrocautery and curettage, chemosurgery, cryosurgery, radiotherapy and topical chemotherapy. Each technique has advantages and disadvantages as listed in a recent article [Martinez, J.-C. and Otley, C. C. (2001), “The management of melanoma and nonmelanoma skin cancer: A review for the primary care physician,” Mayo Clin. Proc. 76, 1253-1265]. Unlike many other cancers, malignant melanoma is notoriously resistant to chemotherapy. Also, while there is some evidence that melanoma may be treated with immune therapy, so far various vaccine therapies, cytokine therapy, or immune cell therapy (such as dendritic cell therapy) have met only with limited success. For example, in advanced melanoma cases only modest antitumor effects were reported with high doses of interferon (IFN)-α2b and interleukin-2, while several other cytokines were ineffective [Atkins, M. B., Elder, D. E., Essner, R., Flaherty, K. T., Gajewsky, T. F., Haluska, F. G., Hwu, P., Keilholz, U., Kirkwood, J. M., Mier, J. W., Ross, M. I., Slingluff, C. L., Sondak, V. K., Sosman, J. A., Weinstock, M. A. and King, L. (2006), “Innovations and challenges in melanoma: Summary statement from the first Cambridge conference,” Clin. Cancer Res. 12 (7 Suppl), 2291s-2296s; Atkins, M. B. (2006), “Cytokine-based therapy and biochemotherapy for advanced melanoma,” Clin. Cancer Res. 12 (7 Suppl), 2353s-2358s]. Furthermore, some cytokines, particularly interleukin-1β (IL-1β), actually promote tumor growth and metastasis [Elaraj, D. M., Weinreich, D. M., Varghese, S., Puhlmann, M., Hewitt, S. M., Carroll, N. M., Feldman, E. D., Turner, E. M. and Alexander, H. R. (2006), “The role of interleukin 1 in growth and metastases of human cancer xenografts,” Clin. Cancer Res. 12, 1088-1096].
Another cytokine that can induce apoptotic cell death is tumor necrosis factor-α (TNF-α) normally produced by macrophages, T lymphocytes and endothelial cells upon inflammatory stimuli [Varfolomeev, E. E. and Ashkenazi, A. (2004), “Tumor necrosis factor: an apoptosis juNKie?,” Cell 116, 491-497]. As it was recently reviewed [Bennloch, M., Mena, S., Ferrer, S., Obrador, E., Asensi, M., Pellicer, J. A., Carretero, J., Ortega, A. and Estrela, J. M. (2006), “Bcl-2 and Mn-SOD antisense oligodeoxynucleotides and glutamine-enriched diet facilitate elimination of highly resistant B16 melanoma cells by tumor necrosis factor-α and chemotherapy,” J. Biol. Chem. 281, 69-79], recombinant TNF-α can induce hemorrhagic necrosis and regression of tumors including melanoma, and it is being utilized for the treatment of patients with locally advanced solid tumors. Unfortunately, delivery of optimal doses of TNF-α is associated with severe toxicity that restricts its administration to sub-optimal doses.
In view of the increasing incidence of skin cancer and the difficulty to treat disseminated melanoma, a large segment of the population would benefit from the use of an agent or a combination of agents capable of inhibiting early stage melanoma and reducing or preventing the occurrence of skin cancer. In order to avoid side effects and simplify the treatment, such agent(s) should preferably act locally on the skin. Presently no effective local treatment can be offered to prevent skin cancer or to treat melanoma patients. Pre-clinical studies performed by others suggest that locally applied inhibitors of Akt kinase and extracellular signal-regulated kinase may be introduced into the clinical practice at some future date [Bedogni, B., O'Neill, M. S., Welford, S. M., Bouley, D. M., Giaccia, A. J., Denko, N. C. and Powell, M. B. (2004), “Topical treatment with inhibitors of the phosphatidylinositol 3′-kinase/Akt and Raf/mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways reduces melanoma development in severe combined immunodeficient mice,” Cancer Res. 64, 2552-2560].